Tetracyclic pyridone compounds as antivirals

• US 9,845,325 B2
• Filed: 02/16/2017
• Issued: 12/19/2017
• Est. Priority Date: 02/19/2016
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Fu, Jiping, Jin, Xianming, Lee, Patrick, Lu, Peichao, Young, Joseph Michael
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US15/435,137
• Publication Number:
  US 20170240548A1
• Time in Patent Office: 306 Days
• Field of Search: 546 1
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 217/08 with a hetero atom directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/147 the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides compounds of Formula (I)

as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by hepatitis B virus, and reducing the occurrence of serious conditions associated with HBV.

Claims

1. A compound of formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is halo.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is H.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is C₁-C₃ alkoxy or halo.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is —

OR¹¹.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is H.

7. The compound of claim 1, which is of the formula:

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is C₁-C₄ alkyl, optionally substituted with up to two groups selected from halo, CN, —

OR, C₁-C₃ haloalkoxy, and a 4-7 membered heterocyclic group containing one or two heteroatoms selected from N, O and S as ring members that is optionally substituted with one or two groups selected from halo, oxo, CN, R, —

OR, and —

NR₂.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is selected from —

CH₂CH₂OMe, —

CH₂CH₂CH₂OMe, —

CH₂—

OEt, —

CH₂CH₂-Q, and —

CH₂CH₂CH₂-Q,

where Q is selected from

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

R⁹ taken together with one group selected from R⁶, R⁷ and R⁸ forms a 4-6 membered cycloalkyl ring or a 5-6 membered heterocyclic ring containing N, O or S as a ring member;

wherein the cycloalkyl or heterocyclic ring is optionally substituted with up to three groups selected from R, —

OR, —

NR₂, halo, CN, COOR, CONR₂, and oxo.

11. The compound of claim 1, which is selected from:

12. The compound of claim 1, wherein R¹ is F.

13. A pharmaceutical composition, comprising a compound of claim 1 admixed with at least one pharmaceutically acceptable carrier.

14. A method to treat a hepatitis B infection, which comprises administering to a patient having a hepatitis B infection a compound of claim 1.

15. The method of claim 14, wherein the compound of claim 1 is used in combination with an additional therapeutic agent selected from an interferon or peginterferon, an HBV polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a capsid assembly inhibitor, an HBV core modulator, a reverse transcriptase inhibitor, a TLR-agonist, or an immunomodulator.